Various structural motifs among homologous proteins are conserved. This represents an evolutionary consequence of preserving effective structures necessary for desired protein functions (Creighton, T. E., PROTEINS: STRUCTURE AND MOLECULAR PROPERTIES, W.H. Freeman and Co., New York, pp 201-269 (1993); and Branden, C. & Tooze, J., INTRODUCTION TO PROTEIN STRUCTURE, Garland Publishing Inc., New York, pp 11-77 (1991)). Consequently, there are common peptide structures in similar or ancestrally-related proteins in different tissues and species (e.g., membranous Ca2+ channel proteins are found in heart, skeletal muscle, nerve, pituitary glands, β-cells of the pancreas and other tissues). See, Hille, B., IONIC CHANNELS IN EXCITABLE MEMBRANES, Sunderland, M.A., Ed., pp 261-389 (1992).
The ion channel proteins in various tissues are encoded by separate genes and have distinct amino acid sequences. Yet the tertiary structure and functional properties of these proteins are very similar or nearly identical. As a result of the common functional properties of ion channel proteins, the domains (or regions) which confer the essential functional properties to ion channel proteins are very highly, and usually absolutely, conserved. As a result, drugs which modulate ion channel proteins are inherently incapable of being directed specifically to specific ion channel proteins in one tissue without affecting other tissues.
Similarly, other homologous classes of proteins exist (e.g., voltage-gated Na+ and K+ channel proteins, lactate dehydrogenase, etc.) and the use of agents developed to modulate the proteins and thus to treat specific diseases often causes undesired side-effects by interacting with the homologous proteins. For example, fast-acting class 1b antiarrhythmics which modify cardiac Na+ channel proteins, are not widely used to treat ventricular arrhythmias because of neurological toxicity which is a consequence of effects of the drugs on nerve Na+ channel proteins (see, Bean, B. P., et al., J. Gen. Physiol. 81:613 (1983) and DeLuca, A., et al., Naunym-Schmiedeberg's Arch. Pharmacol. 344:596 (1991)). In another example, Ca2+ channel protein blockers which are designed as antihypertension agents often cause undesirable side-effects in the brain, cardiac muscle and skeletal muscle. These side-effects are associated with actions of the blockers. In fact, most classes of therapeutic agents are inherently non-specific and invariably modulate homologous proteins.
The specific targeting or anchoring of drugs to a receptor site would be extremely advantageous, particularly if the drug is toxic. Drugs linked to antibodies, in the form of immunoconjugates, have been used to assist in targeted drug delivery (see, B. A. Froesh, et al., Cancer Immunol. Immunother. 42:55 (1996); D. Willner, et al., Bioconjugate Chem. 4:521 (1993)). These strategies have limitations as many cellular sites cannot be targeted with immunoconjugates. Moreover, immunoconjugates are typically delivered by injection, thus limiting their widespread use.
What is needed are new compounds and methods of site-specific delivery of pharmaceutical agents. The new compounds would provide alternatives to immunoconjugates by having targeting or anchoring moieties which are not antibody-based. The present invention provides such compounds and methods of delivery.